Complement drives circuit modulation in the adult brain

Once widely considered an immune-privileged organ, the brain is now known to be intimately intertwined with immune-system activation. In particular, the complement system, an enzymatic cascade conferring innate immunity, has crucial functions for several neurodevelopmental and neuromigratory mechanisms. Recent advances have demonstrated the neurological importance of complement activation in the adult brain, whereby phagocytosis of weakened synapses biologically encodes forgetting of information through complement activation. Neurophysiologically, complement factors can also influence the brain's computational processes, increasing neuronal calcium influx and neurotransmitter release and altering synaptic strength. The complement system's effects on synaptic connectivity can also be observed in many pathological conditions including epilepsy, schizophrenia, and viral-induced cognitive deficits, where perturbations of complement-stimulated synaptic remodelling lead to severe dysfunction. In this review we provide an overview of current knowledge for complement in neurodevelopment, and examine recent evidence highlighting a critical physiological role of complement in the plasticity of the adult brain. This is especially relevant due to the explosion of complementtargeted therapeutics in clinical trials to treat neurological disorders.

Automated summary

The brain is now known to have intimate connections with the immune system, particularly through the complement system. Complement activation plays crucial roles in neurodevelopment and synaptic plasticity in the adult brain. Dysregulation of complement-mediated synaptic remodeling can lead to severe dysfunction in various neurological disorders. Understanding the physiological role of complement in the brain is especially important due to the increasing use of complement-targeted therapeutics in clinical trials.